The present invention relates to novel antagonists of endothelin useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, angina, arrhythmias, asthma, atherosclerosis, benign prostatic hyperplasia, Buerger's Disease, cardiac arrest, cardiogenic shock, cerebral trauma, Chrohn's Disease, congenital heart disease, congestive heart failure (CHF) (mild), congestive heart failure (CHF) (severe), cerebral ischemia, cerebral infarction, cerebral vasospasm, cirrhosis, diabetes, dilated cardiomyopathy, drowning (anoxia), endotoxic shock, gastric mucosal damage, glaucoma, head injury, hemodialysis, hemorrhagic shock, hypertension (essential), hypertension (malignant), hypertension (pulmonary), hypertension (pulmonary, after bypass), hypoglycemia, inflammatory arthritides, ischemic bowel disease, ischemic disease, male penile erectile dysfunction, malignant hemangioendothelioma, myocardial infarction, myocardial ischemia, prenatal asphyxia, postoperative cardiac surgery, prostate cancer, preeclampsia, Raynaud's Phenomenon, renal failure (acute), renal failure (chronic), renal ischemia, restenosis, sepsis syndrome, subarachnoid hemorrhage (acute), surgical operations, status epilepticus, stroke (thromboembolic), stroke (hemorrhagic), Takayasu's arteritis, ulcerative colitis, uremia after hemodialysis, and uremia before hemodialysis.
Endothelin-1 (ET-1), a potent vasoconstrictor, is a 21 amino acid bicyclic peptide that was first isolated from cultured porcine aortic endothelial cells. Endothelin-1, is one of a family of structurally similar bicyclic peptides which include: ET-2, ET-3, vasoactive intestinal contractor (VIC), and the sarafotoxins (SRTXs).
The distribution of the two cloned receptor subtypes, termed ET.sub.A and ET.sub.B, have been studied extensively (Arai H., et al., Nature, 1990;348:730, Sakurai T., et al., Nature, 1990;348:732). The ET.sub.A, or vascular smooth muscle receptor, is widely distributed in cardiovascular tissues and in certain regions of the brain (Lin H. Y., et al., Proc. Natl. Acad. Sci., 1991;88:3185). The ET.sub.B receptor, originally cloned from rat lung, has been found in rat cerebellum and in endothelial cells. The human ET receptor subtypes have been cloned and expressed (Sakamoto A., et al., Biochem. Biphys. Res. Chem., 1991;178:656, Hosoda K., et al., FEBS Lett., 1991;287:23). The ET.sub.A receptor clearly mediates vasoconstriction and there have been a few reports implicating the ET.sub.B receptor in the initial vasodilatory response to ET (Takayanagi R., et al., FEBS Lett., 1991;282:103). However, recent data has shown that the ET.sub.B receptor can also mediate vasoconstriction in some tissue beds (Panek R. L., et al., Biochem. Biophys. Res. Commun., 1992;183(2):566).
The involvement of endothelin has been proven in many human disease states.
Elevated levels of endothelin have been measured in patients suffering from ischemic heart disease (Yasuda M., et al., Amer. Heart J., 1990;119:801-806) and either stable or unstable angina (Stewart J. T., et al., Br. Heart J., 1991;66:7-9).
The degree of elevation of plasma ET levels in patients with heart failure varies from 2-fold to 5-fold (Stewart, et al., Circulation, 1992;85:510-517; Lerman, et al., J. Am. Coll. Cardiology, 1992;20: 849-853). The greatest elevation measured appears to be in congestive heart failure (CHF) patients with marked pulmonary hypertension. The increased level of circulating ET in human congestive heart failure patients also correlated with the severity of the disease observed (Rodeheffer, et al., Am. J. Hypertension, 1991:4:9A; Rodeheffer, et al., Mayo Clin. Prod., 1992;67:719-724).
Many studies have indicated increased plasma levels of ET-1 after acute myocardial infarction (MI) in both animals and humans (Stewart, et al., J. Am. Coll. Cardiol., 1991:18:38-43; Tomoda, et al., Am. Heart J., 1993;125:667-672; Ray, et al., Br. Heart J., 1992;67:383-386; Tsuji, et al., Life Sci., 1991;48: 1745-1749). It has also been reported that the action of ET-1 may be enhanced under the conditions of ischemia (Liu, et al., Biochem. Biophys. Res. Commun., 1989;164:1220-1225).
Several in vivo studies with ET antibodies have been reported in disease models. Left coronary artery ligation and reperfusion to induce myocardial infarction in the rat heart, caused a 4- to 7-fold increase in endogenous endothelin levels. Administration of ET antibody was reported to reduce the size of the infarction in a dose-dependent manner (Watanabe T., et al., "Endothelin in Myocardial Infarction," Nature, (Lond.) 1990;344:114). Thus, ET may be involved in the pathogenesis of congestive heart failure and myocardial ischemia (Margulies K. B., et al., "Increased Endothelin in Experimental Heart Failure," Circulation, 1990;82:2226).
Patients with chronic heart failure were treated with the ET antagonist Bosentan, which was found to improve cardiac performance, concluding that ET is involved in the regulation of vascular tone and that inhibition of its effects may be beneficial in chronic heart failure (Kiowski W., et al., Lancet, 1995;346: 732-36, also J. Am. Coll Cardiol., 1995; special edition 296A:779-1).
Infusion of an endothelin antibody 1 hour prior to and 1 hour after a 60 minute period of renal ischaemia resulted in changes in renal function versus control. In addition, an increase in glomerular platelet-activating factor was attributed to endothelin (Lopez-Farre A., et al., J. Physiology, 1991;444: 513-522). In patients with chronic renal failure as well as in patients on regular hemodialysis treatment, mean plasma endothelin levels were significantly increased (Stockenhuber F., et al., Clin. Sci. (Lond.), 1992;82:255-258).
Studies by Kon and colleagues using anti-ET antibodies in an ischemic kidney model, to deactivate endogenous ET, indicated the peptide's involvement in acute renal ischemic injury (Kon V., et al., "Glomerular Actions of Endothelin In Vivo," J. Clin. Invest., 1989;83:1762).
Other investigators have reported that infusion of ET-specific antibodies into spontaneously hypertensive rats (SHR) decreased mean arterial pressure (MAP), and increased glomerular filtration rate and renal blood flow. In the control study with normotensive Wistar-Kyoto rats (WKY) there were no significant changes in these parameters (Ohno A., Effects of Endothelin-Specific Antibodies and Endothelin in Spontaneously Hypertensive Rats," J. Tokyo Women's Med. Coll., 1991;61:951).
Other studies have demonstrated the usefulness of ET antagonists in maintaining beneficial parameters of renal performance following ischemia-induced injuries (Mino, et al., Eur. J. Pharmacol., 1992;221:77-83; Benigni, et al., Kidney Int., 1993;44:440-444).
ET.sub.A receptor MRNA has been detected in 82% of human meningiomas (J. Clin. Invest., 1995;66:2017-2025 Plasma endothelin-1 levels were dramatically increased in a cancer patient with malignant hemangioendothelioma (Nakagawa K., et al., Nippon Hifuka Gakkai Zasshi, 1990; 100:1453-1456).
Exogenous endothelin-1 is also a prostate cancer mitrogen in vitro. Endothelin levels are significantly elevated in men with metastatic prostate cancer. Every human prostate cancer cell line tested by Nelson et al., (Nature Medicine, 1995;Vol 1(9):944) produced ET-1 MRNA and secreted immunoreactive endothelin.
An ET antagonist, PD 155080 was found to mediate prostate smooth muscle function in vivo, which demonstrated that endothelin antagonists may be useful in the treatment of benign prostatic hyperplasia (Chleko I., et al., Annual Meeting of the American Urological Assn, Orlando, 1996).
The ET receptor antagonist BQ-123 has been shown to block ET-1 induced bronchoconstriction and tracheal smooth muscle contraction in allergic sheep providing evidence for expected efficacy in bronchopulmonary diseases such as asthma (Noguchi, et al., Am. Rev. Respir. Dis., 1992;145(4 Part 2):A858).
Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations indicate a role for ET in renal constriction in preeclampsia (Clark B. A., et al., Am. J. Obstet. Gynecol., 1992;166:962-968).
Plasma immunoreactive endothelin-1 concentrations are elevated in patients with sepsis and correlate with the degree of illness and depression of cardiac output (Pittett J., et al., Ann. Surg., 1991;213(3):262).
In addition, the ET-1 antagonist BQ-123 has been evaluated in a mouse model of endotoxic shock. This ET.sub.A antagonist significantly increased the survival rate in this model (Toshiaki M., et al., 20.12.90. EP 0 436 189 A1).
Endothelin is a potent agonist in the liver eliciting both sustained vasoconstriction of the hepatic vasculature and a significant increase in hepatic glucose output (Gandhi C. B., et al., Journal of Biological Chemistry, 1990;265(29):17432). In addition increased levels of plasma ET-1 have been observed in microalbuminuric insulin-dependent diabetes mellitus patients indicating a role for ET in endocrine disorders such as diabetes (Collier A., et al., Diabetes Care, 1992;15(8):1038).
Infusion of ET-1 produced a sustained, reversible, and salt-dependent hypertension when infused into normal, conscious rats (Mortensen, et al., Hypertension, 1990;15:720-723; Mortensen, et al., FASEB J., 1991;5:A1105).
ET.sub.A antagonist receptor blockade has been found to produce an antihypertensive effect in normal to low renin models of hypertension with a time course similar to the inhibition of ET-1 pressor responses (Basil M. K., et al., J. Hypertension, 1992;10(Suppl. 4):S49). The endothelins have been shown to be arrhythmogenic, and to have positive chronotropic and inotropic effects, thus ET receptor blockade would be expected to be useful in arrhythmia and other cardiovascular disorders (Han S.-P., et al., Life Sci., 1990;46:767).
Recently, an ET.sub.A selective antagonist demonstrated an oral antihypertensive effect (Stein P. D., et al., "The Discovery of Sulfonamide Endothelin Antagonists and the Development of the Orally Active ET.sub.A Antagonist 5-(Dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide," J. Med. Chem., 1994;37: 329-331.
Plasma ET levels are elevated in patients with pulmonary hypertension (Yoshibayashi M., et al., Circulation, 1991;84:2280-2285). Increased expression has been measured indicating local production in the lung. Pulmonary hypertension is associated with the increased expression of endothelin-1 in vascular endothelial cells, suggesting that the local production of endothelin-1 may contribute to vascular abnormalities associated with pulmonary hypertension (Giaid A., et al., N. Engl. J. Med., 1993;328:1732-9). In pulmonary hypertension, ET-1 is the most potent constrictor of airway smooth muscle thus far described in vitro (Pons, et al., J. Pharmacol., 1991;102: 791-796). This response has been blocked by ET.sub.A -receptor antagonists (Abraham, et al., J. Appl. Physiol., 1993;74(5);2537-2542). Endothelin antagonists that block the production of endothelin and hence lower levels of endothelin have shown efficacy in several animal models of pulmonary hypertension. Pulmonary hypoxia increases ET-1 expression in the lung (J. Sure. Res., 1994;57:280-283). For example, BQ-123, Bosentan, and PD 156707 provide protection in a rat hypoxia model of hypertension by lowering the increase in pulmonary vascular resistance and pulmonary arterial pressure (Eddahibi S., et al., Am. J. Physiol., 1995;268:H828-835; Bonvallet S. T., et al., Am. Rev. Rest. Dis., 1993;147:A493; IBC International Conference, R. Bialecki, Feb. 5, 1996, Coronado, Calif.). ET.sub.A -receptor antagonists have been found to prevent and reverse chronic hypoxia-induced pulmonary hypertension in rat (DiCarlo, et al., Am. J. Physiol., 1995;269:L690-L697; Chen, et al., J. Appl. Physiol., 1995;79(6):2122-2131).
There is evidence that suggests the extent of increase in plasma ET-1 levels in patients with pulmonary hypertension may reflect the abnormalities of pulmonary circulation. It has been demonstrated that the pulmonary artery endothelial cells are injured in patients with congenital heart disease (Ishikawa S., et al., J. Thorac. Cardiovasc. Sura., 1995; 110:271-3). Further, in cardiopulmonary bypass operations on patients with congenital heart disease, an immediate postoperative increase in circulating endothelin was observed which may predispose the patient to pulmonary vascular lability and crises in the postoperative period (Komai H., et al., J. Thorac. Cardiovasc. Sura., 1993;106:473-8).
The widespread localization of the endothelins and their receptors in the central nervous system and cerebrovascular circulation has been described (Nikolov R. K., et al., Drugs of Today, 1992;28(5): 303-310). Intracerebroventricular administration of ET-1 in rats has been shown to evoke several behavioral effects. The potent vasoconstrictor action of ETs on isolated cerebral arterioles suggests the importance of these peptides in the regulation of cerebrovascular tone. These factors strongly suggest a role for the ETs in neurological disorders.
The volume of ischemic damage in the cerebral hemisphere of cats following middle cerebral artery occlusion was significantly reduced after the IV administration of PD 156707 (Patel, et al., J. Cardiovasc. Pharmacol., 1995;26(Suppl. 3):S412-S415). Reduction of ischemic brain injury in rats was also demonstrated following oral administration of the endothelin antagonist SB 217242 (Barone, et al., J. Cardiovasc. Pharmacol., 1995;26(Suppl. 3): S404-S407).
Several studies have shown that endothelin levels are elevated in acute and chronic renal failure (Torralbo A., et al., Am. J. Kid. Dis., 1995;25(16):918-923). Data in models of acute renal failure indicate that endothelin plays an important role. An endothelin receptor antagonist Bosentan that can block endothelin production and thereby lower levels has been reported to be effective in models of acute renal ischemia (Clozel M., et al., Nature, 1995;365:759). In dogs, the endothelin receptor antagonist SB 2090670 can attenuate ischemia-induced reductions in glomerular filtration rate and increases in fractional sodium excretion (Brooks D. P., et al, J. Pharmacol. Exo. Ther., 1995). In addition, several antagonists have been shown to block radiocontrast-induced nephrotoxicity (Oldroyd S., et al., Radiology, 1995;196:661-665).
TAK-044 has shown protective effects in a model of acute renal failure in rats (Life Sci., 1994;55(4): 301-310).
The ET.sub.A antagonist BQ-123 has been shown to prevent early cerebral vasospasm following subarachnoid hemorrhage (SAH) (Clozel M. and Watanabe H., Life Sci., 1993;52:825-834; Lee K. S., et al., Cerebral Vasoplasm, 1993:217; and Neurosurgery, 1994;34:108). FR 139317 significantly inhibited the vasoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Nirei H., et al., Life Sci., 1993;52:1869). BQ-485 also significantly inhibited the vasoconstriction of the basilar artery after 7 days in a canine two-hemorrhage model of SAH (Yano, et al., Biochem. Biophys. Res. Commun., 1993; 195:969). Ro 46-2005 (Clozel M., et al., Nature, 1993;365:759) has been shown to prevent early cerebral vasospasm following SAH in the rat with no significant effect on systemic arterial blood pressure. Treatment with Ro 47-0203=Bosentan (Clozel, et al., Circulation, 1993;88(4) part 2:0907) to rabbits with SAH had a 36.+-.7% reduction of basilar artery cross-sectional area compared to sham rabbits. All of these studies show in vivo efficacy of endothelin antagonists in cerebral vasospasm resulting from SAH.
Circulating and tissue endothelin immunoreactivity is increased more than 2-fold in patients with advanced atherosclerosis (Lerman A., et al., New England J. Med., 1991;325:997-1001). Increased endothelin immunoreactivity has also been associated with Buerger's disease (Kanno K., et al., J Amer. Med. Assoc., 1990;264:2868) and Raynaud's phenomenon (Zamora M. R., et al., Lancet, 1990;336:1144-1147).
An increase of circulating endothelin levels was observed in patients that underwent percutaneous transluminal coronary angioplasty (PTCA) (Tahara A., et al., Metab. Clin. Exp., 1991;40:1235-1237.
In an experiment to minimize restenosis following carotid artery balloon angioplasty in rats, the ET receptor antagonist SB 209670 was found to ameliorate neointima formation (Douglas, et al., Circulation Res., 1994;75:190-197).
Local intra-arterial administration of endothelin has been shown to induce small intestinal mucosal damage in rats in a dose-dependent manner (Mirua S., et al., Digestion, 1991;48:163-172; Masuda E., et al., Am. J. Physiol., 1992;262:G785-G790). Elevated endothelin levels have been observed in patients suffering from Crohn's disease and ulcerative colitis (Murch S. H., et al., Lancet, 1992;339:381-384).
The ET receptor antagonist bosentan was found to be an antagonist toward the ET-1-induced changes in gastric mucosal hemodynamics as well as on ET-1-induced gastric ulceration (Lazaratos, et al., Pharmacol. Lett., 1995;56(9):195-200).
Graefe's Arch. Clin. Ex. Ophthalmol, 1995;233(8):484-488 provides data to support the hypothesis that vascular dysfunction may be involved in the pathogenesis of optic nerve damage in normal-tension glaucoma.
Eur. J. Pharmacol., 1996;307(1):69-74 teaches a role for endothelins in penile erection.
Release of eicosanoids and endothelin in an experimental model of adult respiratory distress syndrome (ARDS) is covered in Agents Actions Suppl., Prostaglandins Cardiovasc. Syst., 1992;37:41-6.
Am. Rev. Respir. Dis., 1993;148:1169-1173 teaches venous ET-1 concentrations are massively increased in ARDS as a result of both increased formation and decreased clearance.
Chest, 1993;104:476-80 shows plasma ET-1 levels also positively correlate with right atrial pressure, systolic pulmonary arterial pressure, mean pulmonary arterial pressure, and resistance ratio (pulmonary vascular resistance/systemic vascular resistance) in ARDS.
In chronic obstructive pulmonary disease (COPD) and Cor Pulmonale associated with pulmonary hypertension patients excrete higher amounts of ET-1 compared to healthy subjects. Urinary ET-1 levels are further increased during acute exacerbation of the disease.
ET-1 levels in broncho alveolar lavage fluid from patients with COPD have been reported. ET-1 is involved in pulmonary endothelium damage caused by hypoxia in COPD patients. Pulmonary artery hypertension is the primary cardiovascular complication in COPD. (See Sofia, et al., Respiration, 1994:263-268(61); "Increased 24-Hour endothelin-1 urinary excretion in patients with chronic obstructive pulmonary disease" and Matthay, et al., Medical Clinics of North America, 1990:571-618(74); "Cardiovascular pulmonary interaction in chronic obstructive pulmonary disease with special reference to the pathogenesis and management of Cor Pulmonale."
ET-1 expression is increased in the lung vasculature of patients with pulmonary hypertension contributes to the medial hyperplasia and intimal fibrosis of cryptogenic fibrosing alveolitis. See Giaid, et al., The Lancet, 1993:1550-1554(341) Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis.
In summary, some of the conditions in which ET antagonists may be useful in treatment are as follows: acute respiratory distress syndrome (ARDS), angina, arrhythmias, asthma, atherosclerosis, benign prostatic hyperplasia, Buerger's Disease, cardiac arrest, cardiogenic shock, cerebral trauma, Chrohn's Disease, congenital heart disease, congestive heart failure (CHF) (mild), congestive heart failure (CHF) (severe), cerebral ischemia, cerebral infarction, cerebral vasospasm, chronic obstructive pulmonary diseases, cirrhosis, diabetes, dilated cardiomyopathy, drowning (anoxia), endotoxic shock, gastric mucosal damage, glaucoma, head injury, hemodialysis, hemorrhagic shock, hypertension (essential), hypertension (malignant), hypertension (pulmonary), hypertension (pulmonary, after bypass), hypoglycemia, inflammatory arthritides, ischemic bowel disease, ischemic disease, male penile erectile dysfunction, malignant hemangioendothelioma, myocardial infarction, myocardial ischemia, prenatal asphyxia, postoperative cardiac surgery, prostate cancer, preeclampsia, Raynaud's Phenomenon, renal failure (acute), renal failure (chronic), renal ischemia, restenosis, sepsis syndrome, subarachnoid hemorrhage (acute), surgical operations, status epilepticus, stroke (thromboembolic), stroke (hemorrhagic), Takayasuls arteritis, ulcerative colitis, uremia after hemodialysis, and uremia before hemodialysis.
Allen C. F. H., Frame G. F., Can. J. Research 1932; 6:605 teaches the condensation of methyl and ethyl .alpha.-phenyl-.beta.-(para-substituted)benzoylpropionates with benzaldehyde and piperonal in the presence of sodium methylate, followed by acidification, produces cyclic compounds.
Allen C. F. H., Frame G. F., Normington J. B., Wilson C. V., Can. J. Research 1933;8:137 teaches the condensation of benzaldehyde with methyl and ethyl .alpha.-aryl-.beta.-benzoylpropionates in the presence of sodium methylate, followed by acidification, to give unsaturated ketonic acids.
Allen, C. F., Normington, J. B., Wilson, C. V., Can. J. Research 1934;11:382 recites a number of highly substituted acrylic acids or their lactols.
Allen, C. F. H., Davis, T. J., Stewart, D. W., VanAllan, J. A., Can. J. Chem. 1956;34:926 shows that .alpha. aryl-.beta.-aroylpropionic acids exist in an open-chain configuration while the condensation products of these latter acids with aromatic aldehydes are lactols, refuting his previous article Can. J. Research 1933;8:137.